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    Clinical Trial Results:
    Pharmacokinetics of Intramuscular Adrenaline in Food-Allergic Teenagers - does dose matter? The PIMAT study

    Summary
    EudraCT number
    		 2017-003239-13
    Trial protocol
    		 GB  
    Global end of trial date
    02 Oct 2018

    Results information
    Results version number
    		 v1(current)
    This version publication date
    06 Jun 2022
    First version publication date
    06 Jun 2022
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    PIMAT
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03366298
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Imperial College London
    Sponsor organisation address
    Norfolk Place, London, United Kingdom, W2 1PG
    Public contact
    Turner, IMPERIAL COLLEGE LONDON, 44 02033127754, p.turner@imperial.ac.uk
    Scientific contact
    Turner, IMPERIAL COLLEGE LONDON, 44 02033127754, p.turner@imperial.ac.uk
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    05 Apr 2021
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    02 Oct 2018
    Global end of trial reached?
    Yes
    Global end of trial date
    02 Oct 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To assess the effect of intramuscular self-injection of 300mcg and 500mcg adrenaline on blood levels of adrenaline ("pharmacokinetics") and the effect on the heart (blood pressure, heart rate, cardiac output), in food-allergic teenagers over 40kg, using an auto-injector device.
    Protection of trial subjects
    Local anaesthetic cream for intravenous cannulation, supportive environment in paediatric research unit
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    24 Nov 2017
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United Kingdom: 12
    Worldwide total number of subjects
    12
    EEA total number of subjects
    0
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    12
    Adults (18-64 years)
    0
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 Screening conducted according to protocol. 12 participants screened, all recruited

    Period 1
    Period 1 title
    Overall trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Investigator, Monitor, Subject, Data analyst, Assessor
    Blinding implementation details
    Emerade devices were blinded in terms of dose. EPipen device not blinded as impossible to do so.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Emerade 300 / Epipen 0.3mg / Emerade 500
    Arm description
    		 Visit 1: Emerade 300mcg then Epipen 0.3mg Visit 2: Emerade 500mcg
    Arm type
    		 Experimental

    Investigational medicinal product name
    Emerade 300mcg adrenaline auto-injector
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    as per SMPC

    Investigational medicinal product name
    Emerade 500mcg adrenaline auto-injector
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    As per SMPC

    Investigational medicinal product name
    Epipen 0.3mg adrenaline auto-injector
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    as per SMPC

    Arm title
    		 Epipen 0.3mg / Emerade 300 / Emerade 500
    Arm description
    		 Visit 1: Epipen 0.3mg then Emerade 300mcg Visit 2: Emerade 500mcg
    Arm type
    		 Experimental

    Investigational medicinal product name
    Emerade 500mcg adrenaline auto-injector
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    as per SMPC

    Investigational medicinal product name
    Emerade 300mcg adrenaline auto-injector
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    as per SMPC

    Investigational medicinal product name
    Epipen 0.3mg adrenaline auto-injector
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    as per SMPC

    Arm title
    		 Emerade 500 / Emerade 300 / Epipen 0.3mg
    Arm description
    		 Visit 1: Emerade 500mcg Visit 2: Emerade 300mcg then Epipen 0.3mg
    Arm type
    		 Experimental

    Investigational medicinal product name
    Epipen 0.3mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    As per SMPC

    Investigational medicinal product name
    Emerade 300mcg adrenaline auto-injector
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    as per SMPC

    Investigational medicinal product name
    Emerade 500mcg adrenaline auto-injector
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    as per SMPC

    Arm title
    		 Emerade 500 / Epipen 0.3mg / Emerade 300
    Arm description
    		 Visit 1: Emerade 500mcg Visit 2: Epipen 0.3mg then Emerade 300mcg
    Arm type
    		 Experimental

    Investigational medicinal product name
    Emerade 300mcg adrenaline auto-injector
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    as per SMPC

    Investigational medicinal product name
    Emerade 500mcg adrenaline auto-injector
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    As per SMPC

    Investigational medicinal product name
    Epipen 0.3mg adrenaline auto-injector
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    as per SMPC

    Number of subjects in period 1
    		Emerade 300 / Epipen 0.3mg / Emerade 500 Epipen 0.3mg / Emerade 300 / Emerade 500 Emerade 500 / Emerade 300 / Epipen 0.3mg Emerade 500 / Epipen 0.3mg / Emerade 300
    Started
    3
    3
    3
    3
    Completed
    3
    3
    3
    3

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Overall trial
    Reporting group description
    		 12 subjects recruited, all of whom then participated in the crossover trial

    Reporting group values
    		 Overall trial Total
    Number of subjects
    		 12 12
    Age categorical
    Units: Subjects
        In utero
    		 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0
        Newborns (0-27 days)
    		 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0
        Children (2-11 years)
    		 0 0
        Adolescents (12-17 years)
    		 12 12
        Adults (18-64 years)
    		 0 0
        From 65-84 years
    		 0 0
        85 years and over
    		 0 0
    Age continuous
    Units: years
        median (full range (min-max))
    		 15.4 (13.3 to 18.3) -
    Gender categorical
    Units: Subjects
        Female
    		 5 5
        Male
    		 7 7

    End points

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    End points reporting groups
    Reporting group title
    Emerade 300 / Epipen 0.3mg / Emerade 500
    Reporting group description
    		 Visit 1: Emerade 300mcg then Epipen 0.3mg Visit 2: Emerade 500mcg

    Reporting group title
    Epipen 0.3mg / Emerade 300 / Emerade 500
    Reporting group description
    		 Visit 1: Epipen 0.3mg then Emerade 300mcg Visit 2: Emerade 500mcg

    Reporting group title
    Emerade 500 / Emerade 300 / Epipen 0.3mg
    Reporting group description
    		 Visit 1: Emerade 500mcg Visit 2: Emerade 300mcg then Epipen 0.3mg

    Reporting group title
    Emerade 500 / Epipen 0.3mg / Emerade 300
    Reporting group description
    		 Visit 1: Emerade 500mcg Visit 2: Epipen 0.3mg then Emerade 300mcg

    Subject analysis set title
    Emerade 300mcg
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Emerade 300mmcg

    Subject analysis set title
    Emerade 500mcg
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Emerade 500mcg

    Subject analysis set title
    Epipen 300
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Epipen

    Primary: Plasma Catecholamine Levels (Maximum Concentration, Cmax)

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    End point title
    		 Plasma Catecholamine Levels (Maximum Concentration, Cmax)
    End point description
    Pharmacokinetics (plasma catecholamine levels: Cmax) following intramuscular self-injection of 300mcg and 500mcg adrenaline using an auto-injector device, in food-allergic teenagers over 40kg.
    End point type
    Primary
    End point timeframe
    Overall 0-180mins
    End point values
    		 Emerade 300mcg Emerade 500mcg Epipen 300
    Number of subjects analysed
    12
    12
    12
    Units: pg/ml
        geometric mean (confidence interval 95%)
    218 (132 to 359)
    394 (310 to 500)
    290 (200 to 421)
    Statistical analysis title
    		 Peak plasma adrenaline concentration
    Comparison groups
    Emerade 300mcg v Emerade 500mcg
    Number of subjects included in analysis
    24
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence [1]
    Method
    Parameter type
    		 Bioequivalence comparison
    Point estimate
    1.53
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 1.05
         upper limit
    		 2.22
    Notes
    [1] - Bioequivalence data (ratio of geometric mean with 90% confidence intervals):
    Statistical analysis title
    		 Peak plasma adrenaline concentration
    Comparison groups
    Emerade 300mcg v Epipen 300
    Number of subjects included in analysis
    24
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence [2]
    Method
    Parameter type
    		 Bioequivalence comparison
    Point estimate
    1.03
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.83
         upper limit
    		 1.29
    Notes
    [2] - Bioequivalence data (ratio of geometric mean with 90% confidence intervals):
    Statistical analysis title
    		 Peak plasma adrenaline concentration
    Comparison groups
    Emerade 300mcg v Emerade 500mcg v Epipen 300
    Number of subjects included in analysis
    36
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence [3]
    Method
    Parameter type
    		 Bioequivalence comparison
    Point estimate
    1.36
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 1.03
         upper limit
    		 1.78
    Notes
    [3] - Bioequivalence data (ratio of geometric mean with 90% confidence intervals):

    Primary: Plasma Catecholamine Levels (Time to Maximum Concentration, Tmax)

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    End point title
    		 Plasma Catecholamine Levels (Time to Maximum Concentration, Tmax)
    End point description
    Pharmacokinetics (plasma catecholamine levels: Tmax) following intramuscular self-injection of 300mcg and 500mcg adrenaline using an auto-injector device, in food-allergic teenagers over 40kg.
    End point type
    Primary
    End point timeframe
    0-180 minutes
    End point values
    		 Emerade 300mcg Emerade 500mcg Epipen 300
    Number of subjects analysed
    12
    12
    12
    Units: minutes
        geometric mean (confidence interval 95%)
    9.6 (5.3 to 17.4)
    8.5 (6.1 to 11.8)
    5.9 (4.9 to 7.3)
    Statistical analysis title
    		 Time to peak concentration (first peak)
    Comparison groups
    Emerade 300mcg v Emerade 500mcg
    Number of subjects included in analysis
    24
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence [4]
    Method
    Parameter type
    		 Bioequivalence comparison
    Point estimate
    0.88
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.51
         upper limit
    		 1.5
    Notes
    [4] - Bioequivalence comparison, data are presented as ratio of geometric mean with 90% confidence intervals
    Statistical analysis title
    		 Time to peak concentration (first peak)
    Comparison groups
    Emerade 300mcg v Epipen 300
    Number of subjects included in analysis
    24
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence [5]
    Method
    Parameter type
    		 Bioequivalence comparison
    Point estimate
    0.62
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.38
         upper limit
    		 1.01
    Notes
    [5] - Bioequivalence comparison, data are presented as ratio of geometric mean with 90% confidence intervals
    Statistical analysis title
    		 Time to peak concentration (fir...
    Comparison groups
    Emerade 500mcg v Epipen 300
    Number of subjects included in analysis
    24
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence [6]
    Method
    Parameter type
    		 Bioequivalence comparison
    Point estimate
    1.43
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 1.06
         upper limit
    		 1.93
    Notes
    [6] - Bioequivalence comparison, data are presented as ratio of geometric mean with 90% confidence intervals

    Primary: Plasma Catecholamine Levels (Maximum Concentration, Area-under-curve (AUC))

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    End point title
    		 Plasma Catecholamine Levels (Maximum Concentration, Area-under-curve (AUC))
    End point description
    Pharmacokinetics (plasma catecholamine levels: AUC) following intramuscular self-injection of 300mcg and 500mcg adrenaline using an auto-injector device, in food-allergic teenagers over 40kg. Baseline corrected.
    End point type
    Primary
    End point timeframe
    0-180mins
    End point values
    		 Emerade 300mcg Emerade 500mcg Epipen 300
    Number of subjects analysed
    12
    12
    12
    Units: hr.pg/ml
        geometric mean (confidence interval 95%)
    174 (86 to 354)
    387 (263 to 570)
    203 (142 to 292)
    Statistical analysis title
    		 Area under Plasma adrenaline curve (AUC)
    Statistical analysis description
    Area under Plasma adrenaline curve (AUC) - baseline corrected, 0-180
    Comparison groups
    Emerade 300mcg v Emerade 500mcg
    Number of subjects included in analysis
    24
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence [7]
    Method
    Parameter type
    		 Bioequivalence comparison
    Point estimate
    1.75
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 1.06
         upper limit
    		 2.88
    Notes
    [7] - Bioequivalence comparison, data are presented as ratio of geometric mean with 90% confidence intervals
    Statistical analysis title
    		 Area under Plasma adrenaline curve (AUC)
    Statistical analysis description
    Area under Plasma adrenaline curve (AUC) - baseline corrected, 0-180
    Comparison groups
    Emerade 300mcg v Epipen 300
    Number of subjects included in analysis
    24
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence [8]
    Method
    Parameter type
    		 Bioequivalence comparison
    Point estimate
    0.9
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.65
         upper limit
    		 1.24
    Notes
    [8] - Bioequivalence comparison, data are presented as ratio of geometric mean with 90% confidence intervals
    Statistical analysis title
    		 Area under Plasma adrenaline cu...
    Statistical analysis description
    Area under Plasma adrenaline curve (AUC) - baseline corrected, 0-180
    Comparison groups
    Emerade 500mcg v Epipen 300
    Number of subjects included in analysis
    24
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence [9]
    Method
    Parameter type
    		 Bioequivalence comparison
    Point estimate
    1.9
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 1.41
         upper limit
    		 2.57
    Notes
    [9] - Bioequivalence comparison, data are presented as ratio of geometric mean with 90% confidence intervals

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    1 day
    Adverse event reporting additional description
    Adverse events following self-administration of adrenaline via autoinjector device defined as in protocol
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 per protocol
    Dictionary version
    n/a
    Reporting groups
    Reporting group title
    Emerade 300mcg
    Reporting group description
    		 -

    Reporting group title
    Emerade 500mcg
    Reporting group description
    		 -

    Reporting group title
    Epipen 0.3mg
    Reporting group description
    		 -

    Serious adverse events
    		 Emerade 300mcg Emerade 500mcg Epipen 0.3mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Emerade 300mcg Emerade 500mcg Epipen 0.3mg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    8 / 12 (66.67%)
    9 / 12 (75.00%)
    8 / 12 (66.67%)
    Cardiac disorders
    Palpitations
         subjects affected / exposed
    3 / 12 (25.00%)
    4 / 12 (33.33%)
    3 / 12 (25.00%)
         occurrences all number
    3
    4
    3
    Nervous system disorders
    Tremor
         subjects affected / exposed
    3 / 12 (25.00%)
    7 / 12 (58.33%)
    8 / 12 (66.67%)
         occurrences all number
    3
    7
    8
    General disorders and administration site conditions
    Pain at injection site
         subjects affected / exposed
    8 / 12 (66.67%)
    6 / 12 (50.00%)
    7 / 12 (58.33%)
         occurrences all number
    8
    6
    7
    Systemic AE (any)
         subjects affected / exposed
    4 / 12 (33.33%)
    9 / 12 (75.00%)
    8 / 12 (66.67%)
         occurrences all number
    4
    9
    8

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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